Abstract Preclinical, clinical and epidemiological studies provide compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) have antineoplastic activity and significantly reduce the incidence and risk of death from multiple cancer types, including lung cancer. Unfortunately, the long-term use of NSAIDs for chemoprevention and their potential application for therapy are not recommended because of the risk of potentially fatal side-effects resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. However, numerous investigators have concluded that the pharmacological basis for their antineoplastic activity may not require COX inhibition, which suggests the feasibility of developing safer and more efficacious non-COX inhibitory derivatives for cancer by targeting the underlying mechanism. We have extensively studied the mechanism by which the NSAID, sulindac inhibits tumor cell growth and have reported that this activity results from cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition and the activation of cGMP/protein kinase G signaling to suppress oncogenic ?-catenin/Tcf-transcriptional activity and the synthesis of key proteins, such as cyclin D1 and survivin that drive tumor cell proliferation and survival. Here we show that the cGMP degrading PDE isozyme, PDE10A is a critically important target of sulindac that is elevated in lung tumors and essential for lung tumor cell growth. Guided by molecular modeling using the crystal structure of PDE10, we synthesized a novel series of sulindac derivatives that potently and selectively inhibit lung tumor cell growth without inhibiting COX-1 or COX-2. These compounds have attractive drug-like properties whereby high lung concentrations relative to plasma and other tissues can be safely achieved by oral administration. A lead compound, MCI-048 was identified that displays strong antitumor activity in an orthotopic mouse model of lung cancer. Further analog development to identify a preclinical drug development candidate and studies to better define the role of PDE10 in lung cancer are therefore urgently needed. The following aims are proposed: 1) synthesize a novel series of sulindac derivatives to improve potency and selectivity, 2) evaluate PDE10 and lung tumor cell growth inhibitory activity of sulindac derivatives, 3) evaluate antitumor activity of sulindac derivatives in mouse models of lung cancer, and 4) further define the role of PDE10 in lung cancer. The focus of this project on the development of novel anticancer drugs and target validation for chemoprevention or therapy have the potential to impact individuals at risk of developing lung cancer as well as patients with advanced stage malignant disease.